Acylthioacetyl cephalosporins

ABSTRACT

ACYLTHIOACETYLCEPHALOSPORINS OF THE GENERAL FORMULA   7-(R1-CH(-S-CO-R2)-CO-NH-),2-(R-OOC-),3-(X-CH2-)-2-CEPHEM   WHEREIN R IS HYDROGEN, LOWER ALKYL, ARALKYL, TRI(LOWER ALKYL)SILYL, A SALT FORMING ION, OR THE GROUP   -CH2-OOC-R3   R1 IS HYDROGEN, LOWER ALKYL, CYCLOALKYL, ARALKYL, ARYL OR CERTAIN HETEROCYCLIC GROUPS; R2 IS LOWER ALKYL, CYCLOALKYL, ARYL OR CERTAIN HETEROCYCLIC GROUPS; R3 IS LOWER ALKYL, ARYL OR ARALKYL; AND X IS HYDROGEN, HYDROXY, LOWER ALKANOYLOXY, ARALKANOYLOXY, THE RADICAL OF A NITROGEN BASE, A QUATERNARY AMMONIUM RADICAL, OR TOGETHER X AND R REPRESENT A BOND LINKING CARBON AND OXYGEN IN A LACTONE RING; ARE USEFUL AS ANTIBACTERIAL AGENTS.

3,778,436 ACYLTHIOACETYL CEPHALOSPORINS Uwe Treuner, Regensburg, andHermann Breuer, Burgweinting, Germany, assignors to E. R. Squibb & Sons,Inc., Princeton, NJ.

No Drawing. Filed Sept. 14, 1971, Ser. No. 180,490 The portion of theterm of the patent subsequent to July 24, 1980, has been disclaimed Int.Cl. C07d 99/24 US. Cl. 260--243 C 8 Claims ABSTRACT OF THE DISCLOSUREAcylthioacetylcephalosporins of the general formula R1CH-C ONH-C H-CfiCHn Q .R, N -CH3X ll c wherein R is hydrogen, lower alkyl, aralkyl,tri(lower alkyl)sily1, a salt forming ion, or the group R is hydrogen,lower alkyl, cycloalkyl, aralkyl, aryl or certain heterocyclic groups; Ris lower alkyl, cycloalkyl, aryl or certain heterocyclic groups; R islower alkyl, aryl or aralkyl; and X is hydrogen, hydroxy, loweralkanoyloxy, aralkanoyloxy, the radical of a nitrogen base, aquaternaryammonium radical, or together X and R represent a bond linking carbonand oxygen in a lactone ring; are useful as antibacterial agents.

SUMMARY OF THE INVENTION I This invention relates to newthiocarbouylthioacetylc'ephalosporins of the formula o-on R representshydrogen, lower alkyl, aralkyl, tri(1ower a1kyl)silyl, a salt formingion or the group o -CH2O-i -R3 especially hydrogen, methyl, pivaloyloxy,sodium or potassium; R is hydrogen, phenyl, thienyl, furyl, oxazolyl,isoxazolyl or thiazolyl, especiallyphenyl, R is lower alkyl,especially'methyl or ethyl, or phenyl; R is lower United States Patent 0ice alkyl, preferably methyl or t-butyl; and X is preferably hydrogen oracetoxy.

DETAILED DESCRIPTION OF THE INVENTION The various groups represented bythe symbols have the meanings defined below and these definitions areretained throughout this specification.

The lower alkyl groups are straight or branched chain hydrocarbonradicals having one to eight carbons in the chain, for example, methyl,ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, amyl or the like.

The cycloalkyl groups include saturated and unsaturated cyclichydrocarbon groups having three to seven carbon atoms and up to twodouble bonds, for example, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclobutenyl, cyclopentenyl, cyclohexenyl,cyclw hexadienyl and the like. The five and six carbon members arepreferred and among the unsaturated members the 1,4-cyclohexadienylgroup is preferred.

The aryl groups are monocyclic carbocyclic aryl groups including simplysubstituted members. By way of illustration, this includes the phenylring and simply substituted phenyl containing one to three substituents(preferably only one) such as the halogens (chlorine and bromine beingpreferred), lower alkyl groups such as those defined above, lower alkoxygroups (i.e., lower alkyl groups of the type defined above attached toan oxygen), hydroxy, carboxy and the like. In the case of the last twonamed substituents there is preferably only one, especially in the paraposition of the phenyl. Illustrative are phenyl, 0-, mandp-chlorophenyl, o-, mand p-bromophenyl, 3,4-dichlorophenyl,3,5-dibromophenyl, o-, mand p-tolyl, p-methoxyphenyl, 3,4,5trimethoxyphenyl, p hydroxyphenyl, p-carboxyphenyl and the like.

The aralkyl groups include a monocyclic carbocyclic aryl group attachedto a lower alkyl group, both as defined above. Illustrative are benzyl,o-, mor p-chlorobenzyl, o-, mor p-bromobenzyl, o-, mor p-methylbenzyl,phenethyl, p-chlorophenethyl, 3,5-diethylbenzyl, 3,4,5-trichlorobenzyland the like.

The lower alkanoyloxy, aroyloxy and aralkanoyloxy groups represented byX include the acyl group of acid esters. The lower alkanoyl radicals arethe acyl radicals of lower fatty acids containing alkyl radicals of thetype described above. The lower alkanoyloxy groups include, for example,acetoxy, propionyloxy, butyryloxy and the like. The aroyloxy groups arederived from monocyclic carbocyclic aryl groups of the kind described.Similarly the :aralkanoyloxy groups consist of monocyclic carbocyclicaryl and alkanoyloxy radicals of the type described. X also representsthe radical of an amine, e.g., an alkylamine like methylamine,ethylamine, dimethylamine, tri-- ethylamine, aralkylamine likedibenzylamine, N,N-dibenzylpyridinium, pyridinium, l-quinolinium,l-picolinium, etc. X and R may also join together, as indicated above,to form a bond linking carbon and oxygen in a lactone ring.

The heterocyclic groups represented by R and R are monocyclicheterocyclic radicals (having 5 or 6 atoms exclusive of hydrogen whichare carbon, sulfur, nitrogen and oxygen, no more than two being otherthan carbon), including thienyl, furyl, oxazolyl, isoxazolyl andthiazolyl, as well as these heterocyclics with the substituents halo,lower alkyl (particularly methyl and ethyl), lower alkoxy (particularlymethoxy and ethoxy) or phenyl.

The salt forming ions represented by R may be metal ions, e.g.,aluminum, alkali metal ions such as sodium or potassium, alkaline earthmetal ions such as calcium or magnesium, or an amine salt ion, of whicha number are known for this purpose, for example, dibenzylamine,N,N-dibenzylethylenediamine, methylamine, triethyl amine, procaine,N-ethylpiperidine, etc.

The new acylthioacetylcephalosporins of this invention are produced byreacting a 7-aminocephalosporanic acid compound of Formula II [whichincludes particularly 7- aminocephalosporanic acid (7-ACA), 7 amino 3desacetoxycephalosporanic acid (7-ADCA) and other derivatives] of theformula b-oR ll with an acylthioacetic acid of the formula C-Rz or anactivated derivative of the Formula II. The symbols have the meaningsalready defined.

The activated derivatives referred to include, for example, the reactionproduct with an anhydride forming reagent such as ethylchloroformate,benzoyl chloride, pivaloyl chloride, etc., or withbis-imidazolecarbonyl, dicyclohexylcarbodiimide, p-nitrophenol or thelike.

The reaction between 7-aminocephalosporanic acid compound and theacylthioacetic acid may be effected, for example, by dissolving orsuspending the latter in an inert organic solvent such as chloroform,methylene chloride, dioxane, benzene or the like, and adding, at aboutroom temperature or below, about an equimolar amount of an anhydrideforming reagent, e.g., ethyl chloroformate, benzoylchloride or the like,or other activating compound such as dicyclohexylcarbodiimide, alongwith a salt forming organic base, such as triethylamine, pyridine or thelike, followed, after an interval, by the addition of the7-aminocephalosporanic acid compound. The product of the reaction isthen isolated by conventional procedures, e.g., by concentration orevaporation of the solvent.

When R is the acyloxymethyl group CHz0( -R$ this group may be introducedinto the 7-aminocephalosporanic acid moiety prior to the reaction withthe acylthioacetic acid or the activated derivative by treatment withone to two moles of a halomethyl ester of the formula wherein hal ishalogen, preferably chlorine or bromine, in an inert organic solventsuch as dimethylformamide, acetone, dioxane, benzene or the like, atabout ambient temperature or below.

As an alternative, a product of Formula I may be produced by reacting asalt, e.g., an alkali metal salt, of the formula (V) Me-S-G-Ra with acompound of the formula or derivative thereof. Me represents a metal,hal is halogen, preferably chlorine or bromine and R and R are the sameas above.

The acylthioacetic acid of Formula III may be produced according to thefollowing general method.

(wherein R is hydrogen or lower alkyl) by a procedure analogous toBonner, Jour. Org. Chem. 33, 1831 (1968).

The symbols have the meanings already defined.

Further process details are also provided in the illustrative examples.

Certain of the compounds of this invention may exist in differentoptically active forms. The various stereoisomeric forms as well as theracemic mixtures are within the scope of the invention.

The compounds of this invention have a broad spectrum of antibacterialactivity against both gram positive and gram negative organisms such asStaphylococcus aureus, Salmonella schottmuelleri, Pseudomonasaeruginosa, Proteus vulgaris, Escherichia coli and Streptococcuspyrogenes. They may be used as antibacterial agents in a prophylacticmanner, e.g., in cleaning or disinfecting compositions, or otherwise tocombat infections due to organisms such as those named above, and ingeneral may be utilized in a manner similar to cephalothin and othercephalosporins. For example, a compound of Formula I or aphysiologically acceptable salt thereof may be used in various animalspecies in an amount of about 1 to 200 mg./kg., daily, orally orparenterally, in single or two to four divided doses, to treatinfections of bacterial origin, e.g., 5.0 mg. /kg. in mice.

Oral forms give prompt high blood levels which are maintained forrelatively long periods.

Up to about 600 mg. of a compound of Formula I or a physiologicallyacceptable salt thereof may be incorporated in an oral dosage form suchas tablets, capsules or elixirs or in an injectable form in a sterileaqueous vehicle prepared according to conventional pharmaceuticalpractice.

They may also be used in cleaning or disinfecting compositions, e.g.,for cleaning barns or dairy equipment, at a concentration of about 0.01to 1% by weight of such compounds admixed with, suspended or dissolvedin conventional inert dry or aqueous carriers for application by washingor spraying. They are also useful as nutritional supplements in animalfeeds.

The following examples are illustrative of the invention. Alltemperatures are on the centigrade scale. Additional variations may beproduced in the same manner by appropriate substitution in the startingmaterial.

EXAMPLE 1 DL-7- [2- (Acetylthio -2-phenylacetamido] cephalosporanic acidand salts To 1.8 gm. (5 mmol.) ofDL-7-[a-(bromophenylacetam1do)]-cephalosporanic acid are dissolved in 15ml. of absolute dimethylformamide and then 0.55 g. (5 mmol.) ofpotassium thioacetate in 15 ml. of dimethyl formamide are added withstirring. The temperature of the reaction mixture is controlled bycooling so that it does not exceed 40. After 10 minutes, the reactionsolvent is poured into 350 ml. of cold water and extracted twice with200 ml. portions of ethyl acetate. The ethyl acetate extract is driedover sodium sulfate and the solvent is distilled off in vacuo. The oilyresidue is crystallized by treatment with ether-petroleum ether.DL-7-[Z-(acetylthio)-2-phenylacet am1do]-cephalosporanic acid isobtained in 86% yield, M.P. 40 (dec.). l

5 6 By dissolving the acid in small amount of n-butanol, Example 1,there are obtained DL- 7-[2-benzoylth io)-2- adding an equivalent amountof'potassium 2-ethylhexphenylacetamido]cephalosporanic acid, M.P. 118(dec.) 'anoate', then addingether gives the potassium salt, M.P. and thepotassium salt, M:P.145 (dec.); 7 178 (dec.).j"I'he' sodiumsalt'i'sformed similarly., v The following additional products having theformula M X MP E 2 i 5 (c) in the table are obtained by-the-procedure ofExample 1 by substituting. for the DL 7 7[a-(bromophenylacetamido)]cephalosporanic acid, the starting-"material(a), and for'the potassium thioacetate, the starting material (b) withthe substituents indicated in the table:

l3L-7-[2-(benzoylthio) Z-PhenyIacetamidQIcephaJO- sporanic acid andpotassium salt By substituting 0.8 g. (5 .mmol.) of potassiumthiobenzoate for the potassium thioacctate in the procedure of 0 TABLE ICgH; OCOCH; OJ CHQ 1 7 What is claimed is: v v e lowen allryl,IR -phenylor,lh-phchyhlbwer alkyl; R is 1. 'A compound of the formula halogen,lower alkoxy lower alkyl, hydroxy or carbo 1ry;'an'd X is hydrogen,hydroxy, lower alkanoyloxy, J R -phe'nyl-CO-O, R phenyl-loweralkanoyloxy, lower 5 alkylamine, dibenzylamine;N,N'-dibenzy1pyridinium,V pyridinium,'1-quinolinium, l-picolinum or together X and R are a bondlinking, carbon and oxygen in a lactone ring.

2; A compound as in claim 1 wherein R is phenyl.

OR 3. A compound as in claim 2 wherein R is lower 1 alkyl and R ishydrogen.

4. Alkali metal salt of a compound of claim 2.

5. A compound as in claim 2 wherein R is hydrogen and R is phenyl.

wherein R is hydrogen, lower alkyl, R -phenyl-lower alkyl tri(loweralkyl)silyl,

0 I 6. A compound as in claim 3 wherein R the lower CH H} R' alkylglroup is methyl. or a salt forming ion of the group consisting of 7. Akal metal salt of the compound of claim 5. aluminum, alkali metal,alkaline earth metal, dibenzyl- Alkah metal salt of the compound of clamamine, N,N-dibenzylethylenediamine, methylamine, triethylamine, procaineand N-ethylpiperidine; R is hy- References C'ted drogen, lower alkyl,saturated or unsaturated cyclo- UNITED STATES PATENTS alkyl of 3 to 7carbons, R4-phenyl-lower alkyl, 4- 3,627,760 12/1971 Bickel et a1.260-243 c phenyl or a monocyclic heterocyclic selected from the groupconsisting of thienyl, furyl, oxazolyl, isoxazolyl NICHOLAS S. RIZZO,Primary Examiner and thiazolyl and halo, lower alkyl, lower alkoxy orphenyl substituted members of that group; R is lower US. Cl. X.R.

alkyl, cycloalkyl of 3 to 7 carbons, Rg-phe'nyl or one 424-246 of saidmonocyclic heterocyclics defined above;-R is Z2223? U NITED STATESPATENT OFFICE CERTIFXCATE OF CGRRECTEON Date December 11, 1973 Pa g entNo. 3 5/78 ,436'

Inventor(s) Uwe Treuner and Hermann Breuer It is certified that errorappears in the ebeve-ifientified patent and that said Letters Patent arehereby corrected as Shawn below:

- r- In line 6 of the headnote, delete the terminal date of the patent"July 24, 1980" and substitute October, 23, 1990 Signed and sealed this18th day of Februaty 1975.

(SEAL) Attest t c. MARSHALL DANN RUTH C MASON; Commissioner of PatentsAttestlng off lcer and Trademarks

